ClinVar Miner

Submissions for variant NM_001048174.2(MUTYH):c.1463C>T (p.Pro488Leu) (rs587778542)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131522 SCV000186516 likely benign Hereditary cancer-predisposing syndrome 2019-05-02 criteria provided, single submitter clinical testing In silico models in agreement (benign) ;Intact protein function observed by in vitro/ex vivo assays
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000656914 SCV000226446 uncertain significance not provided 2015-04-09 criteria provided, single submitter clinical testing
GeneDx RCV000656914 SCV000292632 uncertain significance not provided 2017-04-25 criteria provided, single submitter clinical testing This variant is denoted MUTYH c.1547C>T at the cDNA level, p.Pro516Leu (P516L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant, previously reported as MYH 1505C>T (P502L) using an alternate reference sequence, has been observed in at least one individual with colon adenomas as well as in two healthy controls (Fleischmann 2004, Al-Tassan 2004, Morak 2010). In functional studies, this variant showed complementation of functional deficiency, DNA binding, and glycosylase activity similar to wild-type, but reduced binding to protein partner PCNA (Brinkmeyer 2015, Komine 2015). MUTYH Pro516Leu was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. MUTYH Pro516Leu occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available information, it is unclear whether MUTYH Pro516Leu is pathogenic or benign. We consider it to be a variant of uncertain significance. Of note, MUTYH-Associated Polyposis (MAP) is a recessive condition associated with two pathogenic variants on opposite chromosomes in MUTYH.
Invitae RCV000457983 SCV000545757 uncertain significance MYH-associated polyposis 2020-10-23 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 516 of the MUTYH protein (p.Pro516Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with attenuated familial adenomatous polyposis (PMID: 20618354), and in two unaffected individuals (PMID: 14991577, 14579148). This variant is also known as p.P502L in the literature. ClinVar contains an entry for this variant (Variation ID: 134867). Experimental studies in vitro have shown that while this variant has reduced affinity for the MUTYH binding partner PCNA (PMID: 26377631), it does not affect MUTYH nuclear distribution, DNA binding properties, the amount of active protein, or glycosylase activity (PMID: 26377631, 25820570). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000457983 SCV000837742 uncertain significance MYH-associated polyposis 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131522 SCV000903067 benign Hereditary cancer-predisposing syndrome 2017-03-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121602 SCV000919787 likely benign not specified 2021-01-30 criteria provided, single submitter clinical testing Variant summary: MUTYH c.1547C>T (p.Pro516Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251856 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1547C>T has been reported in the literature as a monoallelic variant in at-least one individual affected with APC-mutation negative attenuated familial adenomatous polyposis (AFAP stage III) who reported a negative family history (example, Morak_2010). These report(s) do not provide unequivocal conclusions about association of the variant with MUTYH-Associated Polyposis. At least two publications reporting experimental evidence evaluating an impact on protein function were ascertained in the context of this evaluation (example, Brinkemeyer_2015, Komine_2015). Both these studies showed no damaging effect of this variant reporting similar DNA binding and glycosylase activity to wild-type enzyme (Brinkemeyer_2015) and a functionally retained ability to compliment the deficiency in an Mut Y disrupted E Coli system by monitoring spontaneous mutation rates (Komine_2015). However, a reduced affinity for PCNA (proliferation cell nuclear antigen), a binding partner of MUTYH protein, was also reported (Brinkmeyer_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign/benign, n=2; VUS, n=4). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the lack of unequivocal clinical evidence and supportive functional evidence outlined above, the variant was classified as likely benign.
ITMI RCV000121602 SCV000085799 not provided not specified 2013-09-19 no assertion provided reference population

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